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Medulloblastoma, WNT-activated/SHH-activated: clinical impact of molecular analysis and histogenetic evaluation

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Abstract

Purpose

Medulloblastoma (MDB) is a small cell poorly differentiated embryonal tumor of the cerebellum, which more frequently compromises children. Overall prognosis is favorable, but dependent of stage, histopathological pattern and molecular group. Approximately 30% of the affected patients will die from the disease. WHO 2016 Classification of Tumors of the Central Nervous System (CNS) has been classified MDB into four principal groups: WNT-activated MDB, SHH-activated MDB, group 3 MDB, and group 4 MDB. WNT-activated MDB is associated to monosomy 6, CTNNB1, DDX3X and TP53 mutations, beta-catenin nuclear immunoexpression, and a better prognosis than SHH-activated MDB.

Discussion

WNT-activated tumors account approximately for 10% of cases of MDBs, and are thought to arise from cells in the dorsal brain stem/lower rhombic lip progenitor cells. SHH-activated MDB more frequently arises in the lateral hemispheres of the cerebellum, and clinical outcome in this group is variable. TP53-mutant SHHactivated MDB usually shows the large cell/anaplastic pattern, and can be related to MYCN amplification, GLI2 amplification and 17p loss. TP53-wildtype SHH-activated MDB is more commonly of desmoplastic/nodular morphology, and can be related to PTCH1 deletion and 10q loss. Gene expression and methylation profiling is the gold standard for defining molecular groups of MDB. In immunohistochemistry assays, anti-GAB1 antibody expression is positive in tumors showing SHH pathway activation or PTCH mutation, while positive immunoexpression for YAP1 antibody can be only found in WNT-activated and SHH-activated MDB.

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References

  1. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK et al (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131(6):803–820

    Article  PubMed  Google Scholar 

  2. Batora NV, Sturm, Jones DT, Kool M, Pfister SM, Northcott PA (2014) Transitioning from genotypes to epigenotypes: why the time has come for medulloblastoma epigenomics. Neuroscience 264:171–185

    Article  CAS  PubMed  Google Scholar 

  3. Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ et al (2012) Medulloblastomics: the end of the beginning. Nat Rev Cancer 12(12):818–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Louis DN, Ohgaki H, Wiestler OT, Cevenee WK, et al (2016) Meduloblastoma. In: WHO Classification of Tumors of the Central Nervous System. IARC, Lyon, Revised 4th Edition, p 184–200

  5. Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H et al (2011) Interative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 29(11):1424–1430

    Article  PubMed  Google Scholar 

  6. Kaur K, Kakkar A, Kumar A, Mallick S, Julka PK, Gupta D, Suri A, Suri V, Sharma MC, Sarkar C (2016) Integrating molecular subclassification of medulloblastoma into routine clinical practice: a simplified approach. Brain Pathol 26(3):334–343

    Article  CAS  PubMed  Google Scholar 

  7. Ellison DW, Dalton J, KOcak M, Nicholson SL, Fraga C, Neale G et al (2011) Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 121(3):381–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Huang H, Mahler-Araújo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P et al (2000) APC mutations in sporadic medulloblastomas. Am J Pathol 156(2):433–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhukova N, Ramaswamy V, Remke M, Pfaff E, Shih DJ, Martins DC et al (2013) Sub-group specific prognostic implications of TP53 mutation in meduloblastoma. J Clin Oncol 31(23):2927–2935

    Article  PubMed  PubMed Central  Google Scholar 

  10. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, Kranenburg TA, Hogg T, Poppleton H, Martin J, Finkelstein D, Pounds S, Weiss A, Patay Z, Scoggins M, Ogg R, Pei Y, Yang ZJ, Brun S, Lee Y, Zindy F, Lindsey JC, Taketo MM, Boop FA, Sanford RA, Gajjar A, Clifford SC, Roussel MF, McKinnon PJ, Gutmann DH, Ellison DW, Wechsler-Reya R, Gilbertson RJ (2010) Subtypes of medulloblastoma have distinct developmental origins. Nature 468(7327):1095–1099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schüller U, Heine VM, Mo J, Kho AT, Dillon AK, Han YG et al (2008) Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14(2):123–134

    Article  PubMed  PubMed Central  Google Scholar 

  12. Rausch T, Jones DT, Zapatka M, StÜtz AM, Zichner T, Weischenfeldt J et al (2012) Genome sequencing of pediatric medulloblastoma links catastrophic rearrangements with TP53 mutations. Cell 148(1–2):59–71, 2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Craveiro RB, Ehrhardt M, Velz J, Olschewski M, Goetz B, Pietsch T, Dilloo D (2017) The anti-neoplastic activity of Vandetanib against high-risk medulloblastoma variants is profoundly enhanced by additional PI3K inhibition. Oncotarget 8(29):46915–46927

    Article  PubMed  PubMed Central  Google Scholar 

  14. Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, James CD (1997) Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57(5):842–845

    CAS  PubMed  Google Scholar 

  15. Wolter M, Scharwächter C, Reifenberger J, Koch A, Pietsch T, Reifenberger G (2003) Absence of detectable alterations in the putative tumor suppressor gene BTRC in cerebellar medulloblastomas and cutaneous basal cell carcinomas. Acta Neuropathol 106(4):287–290

    Article  PubMed  Google Scholar 

  16. Taipale J, Beachy PA (2001) The Hedgehog and Wnt signalling pathways in cancer. Nature 411(6835):349–354

    Article  CAS  PubMed  Google Scholar 

  17. Marino S (2005) Medulloblastoma: developmental mechanisms out of control. Trends Mol Med 11(1):17–22

    Article  CAS  PubMed  Google Scholar 

  18. Baeza N, Masuoka J, Kleihues P, Ohgaki H (2003) AXIN1 mutations but not deletions in cerebellar medulloblastomas. Oncogene 22(4):632–636

    Article  CAS  PubMed  Google Scholar 

  19. Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE et al (2005) B eta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. J Clin Oncol 23(31):7951–7957

    Article  CAS  PubMed  Google Scholar 

  20. Onilude OE, Lusher ME, Lindsey JC, Pearson AD, Ellison DW, Clifford SC (2006) APC and CTNNB1 mutations are rare in sporadic ependymomas. Cancer Genet Cytogenet 168(2):158–161

    Article  CAS  PubMed  Google Scholar 

  21. Moxon-Emre I, Taylor MD, Bouffet E, Hardy K, Campen CJ, Malkin D, Hawkins C, Laperriere N, Ramaswamy V, Bartels U, Scantlebury N, Janzen L, Law N, Walsh KS, Mabbott DJ (2016) Intellectual outcome in molecular subgroups of medulloblastoma. J Clin Oncol 34(34):4161–4170

    Article  PubMed  Google Scholar 

  22. Komori T (2017) The 2016 WHO classification of tumours of the central nervous system: the major points of revision. Neurol Med Chir (Tokyo) 57(7):301–311

    Article  Google Scholar 

  23. Keil VC, Warmuth-Metz M, Reh C, Enkirch SJ, Reinert C, Beier D, Jones DTW, Pietsch T, Schild HH, Hattingen E, Hau P (2017) Imaging biomarkers for adult medulloblastomas: genetic entities may be identified by their MR imaging radiophenotype. AJNR Am J Neuroradiol 38(10):1892–1898

    Article  CAS  PubMed  Google Scholar 

  24. Pritchard JI, Olson JM (2008) Methylation of PTCH1, the patched-1 gene, in a panel of primary medulloblastomas. Cancer Genet Cytogenet 180(1):47–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Thomas WD, Chen J, Gao YR, Cheung B, Koach J, Sekyere E, Norris MD, Haber M, Ellis T, Wainwright B, Marshall GM (2009) Patched1 deletion increases N-Myc protein stability as a mechanism of medulloblastomainitiation and progression. Oncogene 28(13):1605–1615

    Article  CAS  PubMed  Google Scholar 

  26. Pizem J, Popovic M, Cör A (2011) Expression of Gli1 and PARP1 in medulloblastoma: an immunohistochemical study of 65 cases. J Neuro-Oncol 103(3):459–467

    Article  CAS  Google Scholar 

  27. Manoranjan B, Venugopal C, McFarlane N, Doble BW, Dunn SE, Scheinemann K, Singh SK (2012) Medulloblastoma stem cells: where development and cancer cross pathways. Pediatr Res 71(4 Pt 2):516–522

    Article  CAS  PubMed  Google Scholar 

  28. Cordeiro BM, Oliveira ID, Alves MT, Saba-Silva N, Capellano AM, Cavalheiro S, Dastoli P, Toledo SR (2014) SHH, WNT, and NOTCH pathways in medulloblastoma: when cancer stem cells maintain self-renewal and differentiation properties. Childs Nerv Syst 30(7):1165–1172

    PubMed  Google Scholar 

  29. Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M et al (2012) Dissecting the genomic complexity underlying medulloblastoma. Nature 488(7409):100–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vaillant C, Valdivieso P, Nuciforo S, Kool M, Schwarzentruber-Schauerte A, Méreau H, Cabuy E, Lobrinus JA, Pfister S, Zuniga A, Frank S, Zeller R (2015) Serpine2/PN-1 is required for proliferative expansion of pre-neoplastic lesions and malignant progression to medulloblastoma. PLoS One 10(4):e0124870

    Article  PubMed  PubMed Central  Google Scholar 

  31. Teo WY, Shen J, Su JM, Yu A, Wang J, Chow WY et al (2013) Implications of tumor location on subtypes of medulloblastoma. Pediatr Blood Cancer 60(9):1408–1410

    Article  PubMed  Google Scholar 

  32. Min HS, Lee JY, Kim SK, Park SH (2013) Genetic grouping of medulloblastomas by representative markers in pathologic diagnosis. Transl Oncol 6(3):265–272

    Article  PubMed  PubMed Central  Google Scholar 

  33. Natarajan S, Li Y, Miller EE, Shih DJ, Taylor MD, Stearns TM, Bronson RT, Ackerman SL, Yoon JK, Yun K (2013) Notch1-induced brain tumor models the sonic hedgehog subgroup of human medulloblastoma. Cancer Res 73(17):5381–5390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Anne SL, Govek EE, Ayrault O, Kim JH, Zhu X, Murphy DA, van Aelst L, Roussel MF, Hatten ME (2013) WNT3 inhibits cerebellar granule neuron progenitor proliferation and medulloblastoma formation via MAPK activation. PLoS One 8(11):e81769

    Article  PubMed  PubMed Central  Google Scholar 

  35. Hovestadt V, Jones DT, Picelli S, Wang W, Kool M, Northcott PA et al (2014) Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510(7506):537–541

    Article  CAS  PubMed  Google Scholar 

  36. Dimitrova V, Arcaro A (2015) Targeting the PI3K/AKT/mTOR signaling pathway in medulloblastoma. Curr Mol Med 15(1):82–93

    Article  CAS  PubMed  Google Scholar 

  37. Shi X, Zhang Z, Zhan X, Cao M, Satoh T, Akira S, Shpargel K, Magnuson T, Li Q, Wang R, Wang C, Ge K, Wu J (2014) An epigenetic switch induced by Shh signalling regulates gene activation during development and medulloblastoma growth. Nat Commun 5:5425

    Article  PubMed  PubMed Central  Google Scholar 

  38. Tech K, Gershon TR (2015) Energy metabolism in neurodevelopment and medulloblastoma. Transl Pediatr 4(1):12–19

    PubMed  PubMed Central  Google Scholar 

  39. Di Magno L, Basile A, Coni S, Manni S, Sdruscia G, D'Amico D et al (2016) The energy sensor AMPK regulates Hedgehog signaling in human cells through a unique Gli1 metabolic checkpoint. Oncotarget 7(8):9538–9549

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ramaswamy V, Taylor MD (2017) Medulloblastoma: from myth to molecular. J Clin Oncol 35(21):2355–2363

    Article  PubMed  Google Scholar 

  41. Mangum R, Varga E, Boué DR, Capper D, Benesch M, Leonard J, Osorio DS, Pierson CR, Zumberge N, Sahm F, Schrimpf D, Pfister SM, Finlay JL (2016) SHH desmoplastic/nodular medulloblastoma and Gorlin syndrome in the setting of Down syndrome: case report, molecular profiling, and review of the literature. Childs Nerv Syst 32(12):2439–2446

    Article  PubMed  Google Scholar 

  42. Han Y, Xiong Y, Shi X, Wu J, Zhao Y, Jiang J (2017) Regulation of Gli ciliary localization and Hedgehog signaling by the PY-NLS/karyopherin-β2 nuclear import system. PLoS Biol 15(8):e2002063

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wen J, Lee J, Malhotra A, Nahta R, Arnold AR, Buss MC, Brown BD, Maier C, Kenney AM, Remke M, Ramaswamy V, Taylor MD, Castellino RC (2016) WIP1 modulates responsiveness to Sonic Hedgehog signaling in neuronal precursor cells and medulloblastoma. Oncogene 35(42):5552–5564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Alimova I, Ng J, Harris P, Birks D, Donson A, Taylor MD, Foreman NK, Venkataraman S, Vibhakar R (2016) MPS1 kinase as a potential therapeutic target in medulloblastoma. Oncol Rep 36(5):2633–2640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pietsch T, Haberler C (2016) Update on the integrated histopathological and genetic classification of medulloblastoma—a practical diagnostic guideline. Clin Neuropathol 35(6):344–352

    Article  PubMed  PubMed Central  Google Scholar 

  46. Klinger PH, Andrade AF, Delsin LE, Queiroz RG, Scrideli CA, Tone LG et al (2017) Inhibition of SHH pathway mechanisms by arsenic trioxide in pediatric medulloblastomas: a comprehensive literature review. Genet Mol Res. https://doi.org/10.4238/gmr16019412

    PubMed  Google Scholar 

  47. Northcott PA, Buchhalter I, Morrissy AS, Hovestadt V, Weischenfeldt J, Ehrenberger T, Gröbner S, Segura-Wang M, Zichner T, Rudneva VA, Warnatz HJ, Sidiropoulos N, Phillips AH, Schumacher S, Kleinheinz K, Waszak SM, Erkek S, Jones DTW, Worst BC, Kool M, Zapatka M, Jäger N, Chavez L, Hutter B, Bieg M, Paramasivam N, Heinold M, Gu Z, Ishaque N, Jäger-Schmidt C, Imbusch CD, Jugold A, Hübschmann D, Risch T, Amstislavskiy V, Gonzalez FGR, Weber UD, Wolf S, Robinson GW, Zhou X, Wu G, Finkelstein D, Liu Y, Cavalli FMG, Luu B, Ramaswamy V, Wu X, Koster J, Ryzhova M, Cho YJ, Pomeroy SL, Herold-Mende C, Schuhmann M, Ebinger M, Liau LM, Mora J, McLendon RE, Jabado N, Kumabe T, Chuah E, Ma Y, Moore RA, Mungall AJ, Mungall KL, Thiessen N, Tse K, Wong T, Jones SJM, Witt O, Milde T, von Deimling A, Capper D, Korshunov A, Yaspo ML, Kriwacki R, Gajjar A, Zhang J, Beroukhim R, Fraenkel E, Korbel JO, Brors B, Schlesner M, Eils R, Marra MA, Pfister SM, Taylor MD, Lichter P (2017) The whole-genome landscape of medulloblastoma subtypes. Nature 547(7663):311–317

    Article  CAS  PubMed  Google Scholar 

  48. Thompson EM, Hielscher T, Bouffet E, Remke M, Luu B, Gururangan S, McLendon RE, Bigner DD, Lipp ES, Perreault S, Cho YJ, Grant G, Kim SK, Lee JY, Rao AAN, Giannini C, Li KKW, Ng HK, Yao Y, Kumabe T, Tominaga T, Grajkowska WA, Perek-Polnik M, Low DCY, Seow WT, Chang KTE, Mora J, Pollack IF, Hamilton RL, Leary S, Moore AS, Ingram WJ, Hallahan AR, Jouvet A, Fèvre-Montange M, Vasiljevic A, Faure-Conter C, Shofuda T, Kagawa N, Hashimoto N, Jabado N, Weil AG, Gayden T, Wataya T, Shalaby T, Grotzer M, Zitterbart K, Sterba J, Kren L, Hortobágyi T, Klekner A, László B, Pócza T, Hauser P, Schüller U, Jung S, Jang WY, French PJ, Kros JM, van Veelen MLC, Massimi L, Leonard JR, Rubin JB, Vibhakar R, Chambless LB, Cooper MK, Thompson RC, Faria CC, Carvalho A, Nunes S, Pimentel J, Fan X, Muraszko KM, López-Aguilar E, Lyden D, Garzia L, Shih DJH, Kijima N, Schneider C, Adamski J, Northcott PA, Kool M, Jones DTW, Chan JA, Nikolic A, Garre ML, van Meir EG, Osuka S, Olson JJ, Jahangiri A, Castro BA, Gupta N, Weiss WA, Moxon-Emre I, Mabbott DJ, Lassaletta A, Hawkins CE, Tabori U, Drake J, Kulkarni A, Dirks P, Rutka JT, Korshunov A, Pfister SM, Packer RJ, Ramaswamy V, Taylor MD (2016) Prognostic value of medulloblastoma extent of resection after accounting for molecularsubgroup: a retrospective integrated clinical and molecular analysis. Lancet Oncol 17(4):484–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Park AK, Lee SJ, Phi JH, Wang KC, Kim DG, Cho BK, Haberler C, Fattet S, Dufour C, Puget S, Sainte-Rose C, Bourdeaut F, Grill J, Delattre O, Kim SK, Park WY (2012) Prognostic classification of pediatric medulloblastoma based on chromosome 17p loss, expression of MYCC and MYCN, and Wnt pathway activation. Neuro-Oncology 14(2):203–214

    Article  CAS  PubMed  Google Scholar 

  50. Schreck KC, Taylor P, Marchionni L, Gopalakrishnan V, Bar EE, Gaiano N, Eberhart CG (2010) The notch target Hes1 directly modulates Gli1 expression and hedgehog signaling: a potential mechanism of therapeutic resistance. Clin Cancer Res 16(24):6060–6070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yu J, Zhao R, Shi W, Li H (2017) Risk factors for the prognosis of pediatric medulloblastoma: a retrospective analysis of 40 cases. Clinics (Sao Paulo) 72(5):294–304

    Article  Google Scholar 

  52. Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B et al (2017) Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell 31(6):737–754 e6

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Eduardo Cambruzzi

  2. Department of Pathology, Santa Rita Hospital, Complexo Hospitalar Santa Casa, Rua Sarmento Leite, 187, 2° andar, Porto Alegre, RS, Brazil

    Eduardo Cambruzzi

  3. Hospital N. Sra. da Conceição, Porto Alegre, RS, Brazil

    Eduardo Cambruzzi

  4. Universidade Luterana do Brasil, Canoas, RS, Brazil

    Eduardo Cambruzzi

  5. Instituto de Cardiologia, Fundação Universitária de Cardiologia, Porto Alegre, RS, Brazil

    Eduardo Cambruzzi

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Cambruzzi, E. Medulloblastoma, WNT-activated/SHH-activated: clinical impact of molecular analysis and histogenetic evaluation. Childs Nerv Syst 34, 809–815 (2018). https://doi.org/10.1007/s00381-018-3765-2

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